RESUMEN
Obesity, an established risk factor for epithelial cancers, remains prevalent in the United States and many other countries. In contrast to positive energy balance states (overweight, obesity), calorie restriction (CR) has been shown to act as a universal inhibitor of tumorigenesis in multiple animal models of human cancer. Unfortunately, the mechanisms underlying the enhancing effects of obesity or the inhibitory effects of CR on cancer etiology remain elusive. Here, we evaluated the impact of dietary energy balance manipulation on epithelial carcinogenesis and identified several potential mechanisms that may account for the differential effects of obesity and CR on cancer. Obesity enhanced tumor promotion during epithelial carcinogenesis, in part, due to altered insulin-like growth factor-1 receptor (IGF-1R)/EGF receptor (EGFR) crosstalk and downstream signaling to effectors such as Akt/mTOR. Obesity-induced changes in cellular signaling subsequently led to altered levels of cell-cycle proteins that favored enhanced epidermal proliferation during tumor promotion. In contrast, CR reduced susceptibility to tumor promotion, attenuated IGF-1R/EGFR crosstalk and downstream signaling, and altered levels of cell-cycle proteins that favored reduced epidermal proliferation during tumor promotion. Collectively, these findings suggest potential targets for the prevention of epithelial cancers, as well as for reversal of obesity-mediated cancer development and progression. Cancer Prev Res; 5(10); 1236-46. ©2012 AACR.
Asunto(s)
Transformación Celular Neoplásica/patología , Metabolismo Energético , Receptores ErbB/metabolismo , Papiloma/patología , Receptor IGF Tipo 1/metabolismo , Neoplasias Cutáneas/patología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Western Blotting , Restricción Calórica , Carcinógenos/toxicidad , Ciclo Celular , Proliferación Celular , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Dieta , Receptores ErbB/genética , Femenino , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos ICR , Obesidad , Papiloma/inducido químicamente , Papiloma/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor IGF Tipo 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Male Hi-Myc mice were placed on three dietary regimens [30% calorie restriction (CR), overweight control (modified AIN76A with 10 kcal% fat), and a diet-induced obesity regimen (DIO) 60 kcal% fat]. All diet groups had approximately similar incidence of hyperplasia and low-grade prostatic intraepithelial neoplasia in the ventral prostate at 3 and 6 months of age. However, 30% CR significantly reduced the incidence of in situ adenocarcinomas at 3 months compared with the DIO group and at 6 months compared with both the overweight control and DIO groups. Furthermore, the DIO regimen significantly increased the incidence of adenocarcinoma with aggressive stromal invasion, as compared with the overweight control group (96% vs. 65%, respectively; P = 0.02) at the 6-month time point. In addition, at both 3 and 6 months, only in situ carcinomas were observed in mice maintained on the 30% CR diet. Relative to overweight control, DIO increased whereas 30% CR reduced activation of Akt, mTORC1, STAT3, and NFκB (p65) in ventral prostate. DIO also significantly increased (and 30% CR decreased) numbers of T-lymphocytes and macrophages in the ventral prostate compared with overweight control. The mRNA levels for interleukin (IL) 1α, IL1ß, IL6, IL7, IL23, IL27, NFκB1 (p50), TNFα, and VEGF family members were significantly increased in the ventral prostate of the DIO group compared with both the overweight control and 30% CR diet groups. Collectively, these findings suggest that enhanced growth factor (Akt/mTORC1 and STAT3) and inflammatory (NFκB and cytokines) signaling may play a role in dietary energy balance effects on prostate cancer progression in Hi-Myc mice.
Asunto(s)
Adenocarcinoma/patología , Restricción Calórica , Dieta , Metabolismo Energético , Próstata/patología , Neoplasias de la Próstata/patología , Adenocarcinoma/etiología , Adenocarcinoma/metabolismo , Animales , Western Blotting , Peso Corporal , Grasas de la Dieta/efectos adversos , Progresión de la Enfermedad , Ingestión de Energía , Técnicas para Inmunoenzimas , Masculino , Ratones , Obesidad/complicaciones , Obesidad/patología , Sobrepeso/complicaciones , Sobrepeso/patología , Próstata/metabolismo , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/fisiología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
Aberrant activation of phosphoinositide-3-kinase (PI3K)/Akt signaling has been implicated in the development and progression of multiple human cancers. During the process of skin tumor promotion induced by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), activation of epidermal Akt occurs as well as several downstream effectors of Akt, including the activation of mTORC1. Rapamycin, an established mTORC1 inhibitor, was used to further explore the role of mTORC1 signaling in epithelial carcinogenesis, specifically during the tumor promotion stage. Rapamycin blocked TPA-induced activation of mTORC1 as well as several downstream targets. In addition, TPA-induced epidermal hyperproliferation and hyperplasia were inhibited in a dose-dependent manner with topical rapamycin treatments. Immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin also significantly decreased the number of infiltrating macrophages, T cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Using a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and TPA as the promoter, rapamycin (5-200 nmol per mouse given topically 30 minutes prior to TPA) exerted a powerful antipromoting effect, reducing both tumor incidence and tumor multiplicity. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited further growth. Overall, the data indicate that rapamycin is a potent inhibitor of skin tumor promotion and suggest that signaling through mTORC1 contributes significantly to the process of skin tumor promotion. The data also suggest that blocking this pathway either alone or in combination with other agents targeting additional pathways may be an effective strategy for prevention of epithelial carcinogenesis.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Anticarcinógenos/uso terapéutico , Carcinógenos/toxicidad , Papiloma/prevención & control , Neoplasias Cutáneas/prevención & control , Acetato de Tetradecanoilforbol/toxicidad , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Western Blotting , Humanos , Hiperplasia/inducido químicamente , Hiperplasia/tratamiento farmacológico , Ratones , Estadificación de Neoplasias , Papiloma/inducido químicamente , Papiloma/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Sirolimus/uso terapéutico , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales CultivadasRESUMEN
Obesity affects more than one third of the U.S. population and is associated with increased risk and/or disease severity for several chronic diseases, including cancer. In contrast, calorie restriction (CR) consistently inhibits cancer across species and cancer types. Differential effects on globally active circulatory proteins, particularly insulin-like growth factor-1 (IGF-1), provide a plausible mechanistic explanation for the energy balance-cancer link. Diet-induced changes in circulating IGF-1 modulate IGF-1R/EGFR activation and downstream signaling to Akt and mTOR. These dietary energy balance effects on signaling ultimately modulate the levels and/or activity of cell cycle regulatory proteins, regulating proliferation, and modulating susceptibility to tumor development. Selective targeting of mTORC1 potently inhibits tumorigenesis in several model systems producing CR mimetic effects. Targeting this and other pathways modulated by dietary energy balance may lead to the development of strategies for cancer chemoprevention and for reversing the effects of obesity on cancer development and progression.
Asunto(s)
Restricción Calórica , Transformación Celular Neoplásica , Células Epiteliales/metabolismo , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Animales , Metabolismo Energético/fisiología , Células Epiteliales/patología , Humanos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
This case study illuminates contextual factors related to the tutor experience when senior students served as tutors for sophomore students in a problem-based learning (PBL) course in a baccalaureate dental hygiene program. Data were collected using various sources and methods. Tutors and administrators were interviewed, those tutored completed an anonymous questionnaire, the tutorial process and tutor training sessions were observed, and related documents were examined. Data analysis included open and axial coding, creation of tutor profiles, and identification of patterns. Tutor training included experiencing the PBL student role, attending class, and weekly seminar sessions facilitated by a tutor supervisor. Analysis revealed that tutor behaviors could be distinguished by the nature of intended actions (e.g., telling, asking, clarifying, acknowledging), emphasis of comments (process, content, social), and facilitation style (directive, suggestive, empowering). Patterns in tutor behavior and attitudes emerged related to comfort or growth and persistence or lenience. Differences in tutor understanding and perception of their role and the purpose of PBL appeared to influence the role the tutor assumed. Other factors that influenced tutor behavior included tutor intentions, tutor training, and environmental factors (e.g., time). The study, incorporating Fishbein's integrative model, suggests points of influence on tutor behaviors.
Asunto(s)
Higienistas Dentales/educación , Mentores , Modelos Educacionales , Aprendizaje Basado en Problemas , Arizona , Consenso , Humanos , Mentores/educación , Estudios de Casos Organizacionales , Aprendizaje Basado en Problemas/métodos , Estudiantes del Área de la Salud , Encuestas y CuestionariosRESUMEN
The erbB family of receptor tyrosine kinases are known to play important roles in normal epithelial development and epithelial neoplasia. Considerable evidence also suggests that signaling through the epidermal growth factor receptor (EGFR) plays an important role in multistage skin carcinogenesis in mice; however, less is known about the role of erbB2. In this study, to further examine the role of both erbB2 and EGFR in epithelial carcinogenesis, we examined the effect of a dual erbB2/EGFR tyrosine kinase inhibitor, GW2974, given in the diet on skin tumor promotion during two-stage carcinogenesis in wild-type and BK5.erbB2 mice. In BK5.erbB2 mice, erbB2 is overexpressed in the basal layer of epidermis and leads to heightened sensitivity to skin tumor development. GW2974 effectively inhibited skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in wild-type and BK5.erbB2 mice, although a more marked effect was seen in BK5.erbB2 mice. In addition, this inhibitory effect was reversible when GW2974 treatment was withdrawn. GW2974 inhibited 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation, which correlated with reduced activation of both the EGFR and erbB2. These results support the hypothesis that both the EGFR and erbB2 play an important role in the development of skin tumors during two-stage skin carcinogenesis, especially during the tumor promotion stage. Furthermore, the marked sensitivity of BK5.erbB2 mice to the inhibitory effects of GW2974 during tumor promotion suggest greater efficacy for this compound when erbB2 is overexpressed or amplified as an early event in the carcinogenic process.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Algoritmos , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Transgénicos , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.
Asunto(s)
Predisposición Genética a la Enfermedad , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Animales , Benzo(a)Antracenos/farmacología , Proliferación Celular , Transformación Celular Neoplásica , Epidermis/metabolismo , Femenino , Ratones , Modelos Biológicos , Neoplasias/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal , Neoplasias Cutáneas/inducido químicamente , Serina-Treonina Quinasas TOR , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
The prevalence of obesity, an established risk factor for several types of cancer, has increased steadily over the past several decades in the United States. New targets and strategies for offsetting the effect of obesity on cancer risk are urgently needed. In the present study, we examined the effect of dietary energy balance manipulation on steady-state signaling in multiple epithelial tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR) pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60 kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks. Relative to the control group, the DIO regimen increased, whereas CR decreased, circulating insulin-like growth factor-I (IGF-I) as has previously been reported. Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited, activation of Akt and mTOR, regardless of epithelial tissue or genetic background. In contrast, activation of AMP-activated protein kinase was modulated by dietary energy balance manipulation in the liver but not in the epidermis or dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR mice also revealed reduced activation of both the IGF-I receptor and epidermal growth factor receptor in CR mice, compared with control mice or mice maintained on the DIO regimen. Taken together, these novel findings suggest that dietary energy balance modulates signaling through cell-surface receptors (i.e., IGF-I receptor and epidermal growth factor receptor), affecting activation of multiple downstream pathways including Akt and mTOR, thus providing important dietary and pharmacologic targets for disrupting the obesity-cancer link.
Asunto(s)
Dieta , Metabolismo Energético/fisiología , Epitelio/metabolismo , Proteína Oncogénica v-akt/fisiología , Proteínas Quinasas/fisiología , Animales , Distribución de la Grasa Corporal , Peso Corporal , Ingestión de Alimentos/fisiología , Femenino , Homeostasis/fisiología , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteína Oncogénica v-akt/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TORRESUMEN
Problem-based learning (PBL) is an instructional method that is gaining popularity in health care education. Rationale for the use of PBL to better prepare health care providers for the future is provided. Implementation of a PBL model into a baccalaureate dental hygiene degree program is described, including examples of activities that may be helpful to others wishing to implement PBL. Preliminary evaluation results indicate positive outcomes in the intended areas of problem solving and critical thinking, team skills, and personal growth.